Project C3

Project Description

Human polymorphonuclear neutrophilic granulocytes (PMN) are of central importance for the defence against invasive Candida albicans infections. The antifungal activity of these cells depends on their state of cellular activation. Consequently, several cytokines including TNF-α, IFN-γ, IL-1α and IL-1β have been shown to be essential for inducing optimal antifungal activity in PMN in vivo, and a close communication between epithelial cells and PMN is required for the induction of protective antifungal immunity in an in vitro infection model. My group has identified the complement activation product C5a as an essential co-stimulus during C. albicans induced, early-phase immune activation in human whole blood. In this project, we will systematically analyse networks of intrinsic modulation of PMN antifungal activity and further characterise the molecular basis of C5a enhanced antifungal PMN activity. For this purpose, established ex vivo infection models for innate immune cells (monocytes, dendritic cells, macrophages, natural killer cells) as well as in vitro infection models for human epithelial and endothelial cells and a whole blood model of infection will be used. By analysing the secretory responses of different host cells and their modulatory effects on PMN antifungal activity we will elucidate inter-cellular communication networks in antifungal immune activation. Supernatants from infected host cells as well as co-infection assays integrating PMN and other cell types will be used to analyse communication between PMN and other host cells. In depth proteomic analyses for selected communication partners of PMN and integration of these data with transcriptomic datasets from other groups in the CRC/Transregio will then identify potential signalling molecules. Using established activation assays we will systematically address the molecular pathways and receptors involved in modulating PMN activity to get a better understanding of secondary stimuli involved in triggering antifungal activity in PMN. Mutant C. albicans strains with highly attenuated ability to directly activate PMN (e.g. C. albicans Δefg1, Δcph1) and bioinformatical modelling will facilitate analysis of the interplay between primary and secondary signals for PMN activation and dissection of the contribution of different cascades to PMN activation in fungal infection. In summary, this project aims at (i) analysing intrinsic immune-networks in antifungal activation of PMN, (ii) characterising the secretomes of host cell types directly modulating PMN activity, (iii) identifying specific communication signals and (iv) identifying receptors and signalling pathways involved in modulating antifungal PMN activity.

Principal Investigator

Prof. Dr. Oliver Kurzai
Prof. Dr. Oliver Kurzai

Center for Innovation Competence (ZIK) Septomics  
Research group Fungal Septomics  

Friedrich Schiller University Jena

oliver.kurzai@leibniz-hki.de

Publications

Author Year Title Journal Links

Hünniger K, Lehnert T, Bieber K, Martin R, Figge MT, Kurzai O

2014

A virtual infection model quantifies innate effector mechanisms and Candida albicans immune escape in human blood.

PLoS Comput Biol 10: e1003479 PubMed
Dix A, Hünniger K, Weber M, Guthke R, Kurzai O, Linde J 2015 Biomarker-based classification of bacterial and fungal whole-blood infections in a genome-wide expression study. Front Microbiol 6: 171 PubMed
Linde J, Duggan S, Weber M, Horn F, Sieber P, Hellwig D, Riege K, Marz M, Martin R, Guthke R, Kurzai O 2015 Defining the transcriptomic landscape of Candida glabrata by RNA-Seq. Nucleic Acids Res 43: 1392-406 PubMed
Duggan S, Leonhardt I, Hünniger K, Kurzai O 2015

Host response to Candida albicans bloodstream infection and sepsis.

Virulence 6: 316-26 PubMed
Leonhardt I, Spielberg S, Weber M, Albrecht-Eckardt D, Bläss M, Claus R, Barz D, Scherlach K, Hertweck C, Löffler J, Hünniger K, Kurzai O 2015

The fungal quorum-sensing molecule farnesol activates innate immune cells but suppresses cellular adaptive immunity.

mBio 6(2): e00143 PubMed
Hünniger K, Bieber K, Martin R, Lehnert T, Figge MT, Löffler J, Guo RF, Riedemann NC, Kurzai O 2015

A second stimulus required for enhanced antifungal activity of human neutrophils in blood is provided by anaphylatoxin C5a.

J Immunol 194: 1199-210 PubMed

Jacobsen ID, Lüttich A, Kurzai O, Hube B, Brock M

2014

In vivo imaging of disseminated murine Candida albicans infection reveals unexpected host sites of fungal persistence during antifungal therapy.

J Antimicrob Chemother 69: 2785-96

PubMed
Brandes S, Mokhtari Z, Essig F, Hünniger K, Kurzai O, Figge MT 2015 Automated segmentation and tracking of non-rigid objects in time-lapse microscopy videos of polymorphonuclear neutrophils. Med Image Anal 20: 34-51 PubMed
Duggan S, Essig F, Hünniger K, Mokhtari Z, Bauer L, Lehnert T, Brandes S, Häder A, Jacobsen ID, Martin R, Figge MT, Kurzai O 2015 Neutrophil activation by Candida glabrata but not Candida albicans promotes fungal uptake by monocytes. Cell Microbiol 17: 1259-76 PuMed
Lehnert T, Timme S, Pollmächer J, Hünniger K, Kurzai O, Figge MT 2015 Bottom-up modeling approach for the quantitative estimation of parameters in pathogen-host interactions. Front Microbiol 6: 608 PubMed
Wartenberg A, Linde J, Martin R, Schreiner M, Horn F, Jacobsen ID, Jenull S, Wolf T, Kuchler K, Guthke R, Kurzai O, Forche A, d'Enfert C, Brunke S, Hube B 2014

Microevolution of Candida albicans in macrophages restores filamentation in a nonfilamentous mutant.

PLoS Genet 10: e1004824

PubMed
Böhringer M, Pohlers S, Schulze S, Albrecht-Eckardt D, Piegsa J, Weber M, Martin R, Hünniger K, Linde J, Guthke R, Kurzai O 2016 Candida albicans infection leads to barrier breakdown and a MAPK/NF-κB mediated stress response in the
intestinal epithelial cell line C2BBe1.
Cell Microbiol 18: 889-904 Cell Microbiol
Moyes DL, Wilson D, Richardson JP, Mogavero S, Tang SX, Wernecke J, Höfs S, Gratacap RL, Robbins J, Runglall M, Murciano C, Blagojevic M, Thavaraj S, Förster TM, Hebecker B, Kasper L, Vizcay G, Iancu SI, Kichik N, Häder A, Kurzai O, Luo T, Krüger T, Kniemeyer O, Cota E, Bader O, Wheeler RT, Gutsmann T, Hube B, Naglik JR 2016

Candidalysin is a fungal peptide toxin critical for mucosal infection.

Nature 532: 64-8 PubMed
Hellwig D, Voigt J, Bouzani M, Löffler J, Albrecht-Eckardt D, Weber M, Brunke S, Martin R, Kurzai O, Hünniger K 2016 Candida albicans induces metabolic reprogramming in human NK cells and responds to perforin with a zinc depletion Response. Front Microbiol 7: 750 PubMed
Czakai K, Leonhardt I, Dix A, Bonin M, Linde J, Einsele H, Kurzai O, Loeffler J 2016

Krüppel-like Factor 4 modulates interleukin-6 release in human dendritic cells after in vitro stimulation with Aspergillus fumigatus and Candida albicans

Sci Rep 6: 27990 PubMed
Fliesser M, Morton O, Bonin M, Ebel F, Hünniger K, Kurzai O, Einsele H, Löffler J 2015 Hypoxia-inducible factor 1α modulates metabolic activity and cytokine release in anti-Aspergillus fumigatus immune responses initiated by human dendritic cells. Int J Med Microbiol 305: 865-73 PubMed
Beitzen-Heineke A, Bouzani M, Schmitt A, Kurzai O, Hünniger K, Einsele H, Loeffler J 2016

Human invariant natural killer T cells possess immune-modulating functions during Aspergillus infection.

Med Mycol 54: 169-76

PubMed

Dix A, Czakai K, Leonhardt I, Schäferhoff K, Bonin M, Guthke R, Einsele H, Kurzai O, Löffler J, Linde J

2017 Specific and novel microRNAs are regulated as response to fungal infection in human dendritic cells. Front Microbiol 8: 270 PubMed